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Three Part Question

In a [paediatric patient with status asthmaticus not responding to standard therapy] does [the use of intravenous ketamine] provide [benefit]?

Clinical Scenario

A child attends the emergency department with a life threatening exacerbation of asthma. Despite the use of standard therapies the patient continues to deteriorate. You are aware of the bronchodilatory properties of ketamine and consider whether it may be of use as an additional therapy.

Search Strategy

1. Medline (1946-present), EMBASE (1980-present) and CINHAL (1981-present) were searched with use of the HDAS interface with the search criteria 'ketamine' AND (asthma OR asthmatic OR status asthmaticus OR life threatening asthma OR ever asthma OR reactive airways disease OR bronchospasm OR Bronchoconstriction)).ti.ab LIMIT to human and english language.
2. The Cochrane library was accessed and searches made of the Cochrane database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Cochrane central register of controlled trials.
3. British Library EthOS
4.Clinical trials.gov
5. Manual search of reference lists
6. Authors of the primary studies were contacted

Search Outcome

Strategy 1 yielded 147 papers narrowed to 3 case reports 2 randomized trials and one prospective observational trial. Others were excluded based on bronchospasm due conditions other than asthma, review articles and ketamine not studied in isolation.
Strategies 2-6 did not identify any additional papers of relevance to the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Petrillo T, Fortenberry J, Lizner J, Simon H October 2000	10 patients aged 5-16 years were recruited from 2 emergency departments over 3 months with an exacerbation of asthma.	Prospective observational study. 10 patients aged 5-16 received 1mg/kg bolus followed by 0.75mg/kg/hour of ketamine.	Clinical asthma score	Reduced from 14.5 to 9.5 (p<0.001)	* Small sample size * All patients recruited by the same clinicians * Variable treatments received prior to study entry producing a heterogeneous baseline * Patients excluded if deemed 'too ill' by study investigator despite this being the cohort of interest. 'Too ill' also likely to have inter-rater variability * No comparator group * Non blinded * CAS used within the study described as 'modified' - no description of how modified.
			Peak expiratory flow	Increased from 16-69% predicted (p<0.02)
			SpO2	Improved
Allen J, Macias C 2005	68 patients aged 2-18 years received 0.2mg/kg bolus followed by 0.5mg/kg/hour infusion of ketamine for 2 hours	68 patients were recuited with a calculated power of 80% and a alpha of 0.05. Therepy was standardized before study entry and ketamine studied in isolation. Pulmonary index score was used as the primary outcome measure which had previously been identified by Scarfone et al as a reliable indicator of asthma severity.	Pulmonary index score	No statistically significant improvement	* Only one clinical investigator used for recruitment and scoring. * Limited to convenience sample when investigator present Pulmonary index score not widely used * 3 patients were removed from the study due to significant improvement despite this being the objective of the study
Tiwari A, Guglani V, Jat K 2014	48 patients aged between 1-12 years were randomized to receive a 0.5mg/kg bolus followed by 0.6 mg/kg/hour infusion of ketamine for 3 hours.	Randomized parallel group open label trial. Ketamine directly compared to aminophylline.	PRAM score		* Single centre study * No control group
Fischer M 1977	9 year old boy with refractory bronchospasm	Single case report of 9 year old with refractory bronchospasm who received 200mg bolus of ketamine with subsequent improvement in clinical condition.	Arterial blood gases	Improvement	Single patient case report only
Denmark T, Crane H, Brown L 2006	Two paediatric patients aged 9 and 14	Two patients with severe asthma non responsive to conventional treatment received 2mg/kg bolus of ketamine followed by an infusion at 2-3mg/kg/hour with clinical improvement.	Respiratory rate	Improvement	* Single centre * Case reports only * No objective data for improvement in outcome markers * No criteria for when ketamine initiated
			Work of breathing	Improvement
Strube P, Hallam P 1986	13 year old girl admitted with life threatening asthma	13 year old girl with life threatening asthma non responsive to standard therapies treated with 1.5mg/kg ketamine bolus followed by infusion at 2.6mg/kg/hr with clinical improvement.	Arterial bloods gases	Improvement	* Single patient case report * Patient rendered unconscious on therapy however with no loss of airway
			Wheeze	Improvement
			Respiratory rate	Improvement

Comment(s)

It is currently estimated there are 1.1 million children with asthma in the UK accounting for 1 in every 11 children. The UK has one of the highest asthma prevalence rates and despite advances in the understanding of the pathophysiology of asthma there were 1,167 deaths secondary to asthma in 2011, 18 of these being in children aged under 14. Therefore it is important to identify any potential drugs which may confer benefit to those with life threatening asthma exacerbations. Ketamine is known to be a potent bronchodilator based upon research in both humans and animal models. Several case reports have been published highlighting the potential benefit of ketamine with two randomised trials and one prospective observational trial found upon literature search. Petrillo et al identified improvement with a 1mg/kg bolus of ketamine followed by a 0.75mg/kg/hour infusion which obviated the need for intubation. Tiwari et al has further identified that Ketamine has a similar clinical effect to that of aminophylline however was not statistically better than aminophylline in the treatment of asthma. Allen et al did not identify any improvement however the dose of ketamine used was small at only 0.2mg/kg as compared to the other trials. These studies in combination with published case reports would suggest that ketamine may be of potential benefit to a paediatric patient with a life threatening exacerbation of asthma however there is currently insufficient evidence to recommend its routine use. There is however potential for a well designed RCT to address this question.

Clinical Bottom Line

Several studies and case reports highlight the potential benefit of ketamine in asthma however there is insufficient evident to recommend its routine use.

References

1. Petrillo T, Fortenberry J, Lizner J, Simon H Emergency department use of ketamine in paediatric status asthmaticus Journal of asthma 2001 volume 38(8) p657-664
2. Allen J, Macias C The efficacy of ketamine in paediatric emergency department patients who present with acute severe asthma Annals of emergency medicine 2005 vol 46(1) 43-50
3. Tiwari A Ketamine versus aminophylline for status asthmatic children: A randomized controlled trial European respiratory journal 2014 vol 44(58) 281
4. Fischer M Ketamine Hydrochloride in severe bronchospasm Anaesthesia 1977 vol 32 771-772
5. Denmark T Ketamine to avoid ventilation in severe paediatric asthma Journal of emergency medicine 2006 vol 30 163-166
6. Strube P Ketamine by continuous infusion in status asthmaticus Anaesthesia